ACTHAR GEL for Sarcoidosis-Associated Calcium Dysregulation: An Open-label Pilot Study

Sarcoidosis is a multisystem granulomatous disease of unknown cause. Although sarcoidosis most commonly affects the lung, it may affect any organ. Although corticosteroids are recognized as the drug of choice for sarcoidosis. ACTH(adrenocorticotropic hormone) is the only drug that is FDA-approved for this disorder. However, there is limited data on the efficacy of ACTH for this condition.

Calcium metabolism is disregulated in active sarcoidosis. The primary abnormality in calcium metabolism stems from an increased 1-α hydroxylase activity in sarcoid alveolar macrophages that converts 25-hydroxyvitamin D to 1, 25-dihydroxyvitamin D, the active form of the vitamin. This can result in hypercalcemia, hypercalciuria, nephrocalcinosis, nephrolithiasis, interstitial nephritis, glomerulonephritis, acute and chronic kidney disease. Importantly, almost of the renal manifestations stem from disordered calcium metabolism. Unlike other organ manifestations of sarcoidosis, the disorder of calcium metabolism is more common in whites compared to african americans.Compared to hypercalcemia, hypercalciuria is three times more common in sarcoidosis, nevertheless, it has largely been ignored.

In general, the patient with hypercalcemia should be advised to avoid sunlight, curtail intake of major sources of dietary calcium and vitamin D, and drink ample fluids.If the patient is symptomatic, serum calcium is greater than 11 mg/dl, the serum creatinine is elevated, or the patient has nephrolithiasis, drug therapy is usually required. The drug of choice is prednisone at an initial daily dose of 20 - 40 mg/day.Unfortunately, prolonged corticosteroid therapy may result in unacceptable side effects including osteoporosis. This is particularly important as elevated calcitriol observed in patients with sarcoidosis can further jeopardize bone structure by resorption. Alternative medications that have shown benefit for sarcoidosis associated calcium dysregulation have included chloroquine,hydroxychloroquine, ketoconazole.

Not only may ACTHER GEL have obvious anti-inflammatory effects by resulting in corticosteroid production, but it may also activate melanocortin receptors. The melanocortin system has powerful anti-inflammatory properties that may be beneficial in the treatment of sarcoidosis.

We believe that there are several specific advantages of assessing the effectiveness of anti-sarcoidosis therapy by examining sarcoidosis-associated disorders of calcium metabolism.

1. The measures of granulomatous activity (serum calcium, urinary calcium, serum 25-hydroxyvitamin D, and serum 1, 25-dihydroxyvitamin D levels) are directly related to the granulomatous inflammation of sarcoidosis.
2. These parameters can be accurately and objectively quantified. This is an important issue in sarcoidosis as the endpoint for involvement of the lungs, skin, and eyes is problematic because it is either inexact and/or not unidimensional.

3. These constituents can be easily used to clinically monitor sarcoidosis. This is not the case for other forms of sarcoidosis including involvement of the lung and skin.

   • Although hypercalciuria and disordered calcium metabolism is not as common a manifestation of sarcoidosis as lung involvement, there is little evidence that the anti-granulomatous response to this disease is organ specific. In a randomized double-blind placebo control trial of infliximab for pulmonary sarcoidosis, extrapulmonary sarcoidosis also responded to this therapy.